Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for type 2 diabetes and obesity, delivering robust metabolic and cardiovascular benefits. However, their potential impact on tumori Show more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for type 2 diabetes and obesity, delivering robust metabolic and cardiovascular benefits. However, their potential impact on tumorigenesis remains debated. Preclinical findings in rodents have suggested that GLP-1R activation may influence thyroid C-cells and pancreatic ducts, while human studies have yielded inconsistent cancer risk signals. This review synthesizes current evidence on GLP-1R and glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling in cancer biology, emphasizing the role of biased agonism and context-dependent effects. GLP-1R activation, predominantly via cAMP/PKA signaling, has shown antiproliferative effects in gastrointestinal adenocarcinomas and pancreatic ductal adenocarcinoma models, whereas GIPR activation frequently engages PI3K/Akt (PI3K, phosphoinositide 3-kinase; Akt, protein kinase B) and ERK/MAPK cascades (ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase), enhancing proliferation in colorectal and neuroendocrine tumors. Conversely, GLP-1R stimulation can promote growth in GLP-1R-high neuroendocrine tumors, reflecting ligand- and tissue-specific signaling biases. Beyond direct tumor cell effects, GLP-1RAs modulate the tumor microenvironment by reducing NF-κB-driven inflammation, altering stromal activity, and potentially enhancing immune surveillance. Current clinical evidence does not support a generalized increase in cancer risk with GLP-1RA therapy; benefits in metabolic control may even reduce obesity-related cancer incidence. Nonetheless, caution is advised in patients with medullary thyroid carcinoma, MEN2, or GLP-1R-high neuroendocrine tumors. The emerging paradigm suggests precision approaches, integrating receptor profiling, biased agonist design, and risk stratification, will be key to safely leveraging incretin-based therapies in oncology. Show less
The orbitofrontal cortex (OFC) is a vital component of brain reward circuitry that is important for reward seeking behavior. However, OFC-mediated molecular mechanisms underlying rewarding behavior ar Show more
The orbitofrontal cortex (OFC) is a vital component of brain reward circuitry that is important for reward seeking behavior. However, OFC-mediated molecular mechanisms underlying rewarding behavior are understudied. Here, we report the first circular RNA (circRNA) profile associated with appetitive reward and identify regulation of 92 OFC circRNAs by sucrose self-administration. Among these changes, we observed downregulation of circNrxn3, a circRNA originating from neurexin 3 (Nrxn3), a gene involved in synaptogenesis, learning, and memory. Transcriptomic profiling via RNA sequencing and qPCR of the OFC following in vivo knock-down of circNrxn3 revealed differential regulation of genes associated with pathways important for learning and memory and altered splicing of Nrxn3. Furthermore, circNrxn3 knock-down enhanced sucrose self-administration and motivation for sucrose. Using RNA-immunoprecipitation, we report binding of circNrxn3 to the known Nrxn3 splicing factor SAM68. circNrxn3 is the first reported circRNA capable of regulating reward behavior and circNrxn3-mediated interactions with SAM68 may impact subsequent downstream processing of RNAs such as the regulation of gene expression and splicing. Show less